Method of producing 1,3,4-thiadiazol-2-ylureas

ABSTRACT

Certain 2-alkylamino-1,3,4-thiadiazole compounds are reacted with N,N-dialkylcarbamoyl chlorides in the presence of sodium metalating agents to provide fully substituted 1,3,4-thiadiazol2-ylurea compounds.

United States Patent [191 Cebalo [451 Aug. 12, 1975 METHOD OF PRODUCINGl ,3,4-THIADlAZOL-2-YLUREAS [75] Inventor: Tony Cebalo, Allentown, Pa.

[73] Assignee: Air Products and Chemicals, Inc.,

Allentown, Pa.

[22] Filed: Jan. 19, 1970 [21] App]. N0.: 4,075

[52] US. Cl 260/306.8 D; 71/90; 260/999 [51] Int. Cl. ..C07d 91/62 [58]Field of Search 260/306.8 D

[56] References Cited UNITED STATES PATENTS 3,565,901 2/ 1 971 Cebalo260/306.8

Primary Examiher-Richard J. Gallagher Attorney, Agent, or Firm-LeroyWhitaker 57 ABSTRACT 6 Claims, No Drawings METHOD OF PRODUCINGI,3,4-TI-IIADIAZOL-Z-YLUREAS BACKGROUND OF TI-IE INYENTION It isgenerally known in the art to react N,N-dialkylcarbamoyl chlorides withamines in the presence of an acid acceptor (e'.g. triethylaminepyridine, potassium carbonate, etc.) to produce urea compounds. However,such reactions do not provide the desirable urea compounds produced bythe method of the invention I since the 2-alkylaminol ,3,4-thiadiazoleintermediates required to give the urea product of the invention areunreactive in such reactions. Furthermore, it is known that certainpreformed metal derivatives of amines (e.g. sodium, potassium, lithium,etc.) will react with N,N-dialkylcarbamoyl chlorides to produce ureacompounds. However, this reaction will only work for certainZ-alkylaminol ,3,4-thiadiazole intermediates while for others extremelypoor or no yields of the desired urea products are obtained.

thiadiazole compound with an N,N-dialkyl carbamoyl chloride compound inthe presence of a sodium metalating agent to obtain a l,3.4-thiadiazol-2ylurea compound.

PREFERRED EMBODIMENTS OF THE INVENTION The method of the invention maybe represented by the following general reaction:

The 2-alkylamino-l,3,4-thiadiazole compounds (X) employed in (II) abovemay be produced by methods generally known in the art. Examples of suchmethods are as follows:

rm (1) 1 00011 a mncum The above reaction uses polyphosphoric acid (PIA)as a dehydrating agent.

ZNNHCNHRZ R CNHNEICP-IHR or CF3COOH ll S O n n ncs R rfiuumucuun cone H80 c. EHCNHNHCNHR X I] or PPA O S P01 (3) r't cOCl H .tixll lCh ll-lli XSUMMARY OF THE INVENTION The present invention is directed to a methodfor producing l,3,4-thiadiazol-2-ylurea compounds having the generalstructure:

2-alkylamino-l ,3,4-

In each of the equations (1), (2) and (3 R and R are as defined above.Any of the above methods will yield the compound (X). For givensubstituents R and R each of the above methods will give a differentyield. Selection of the preferred method, consequently, is an empericaldecision based on experience with given substituents. Choice of methodwill be obvious to those skilled in the art, having the above disclosurebefore them.

The compound of structure (X) is reacted with an N,N-dialkylcarbamoylchloride, in an inert solvent, with the aid of sodium metalatingagentsfi lt is essential to the method of the invention that the sodiummetalating agent be added very slowly to the reaqtion mixture containingthe compound of structure ,(X) and the N,N-dialkylcarbamoyl chloride.Such sipw addition provides for controlled formation of the sodiumderivative of the Z-alkylamino-l ,3,4-thiadiazole which in turn reactswith the N,N-dialkylcarbamoyl chloride to produce the desiredl,3,4-thiadiazol-2-ylurea compounds. Slow addition of the metalatingagents eliminates the presence of a large excess of the sodiumderivative which in turn readily decomposes. This presence of a largeexcess of the sodium derivative causes a considerable decrease in theyield of the desired product and in some cases no yield at all isobtained.

The N,N-dialkylcarbamoyl chlorides that may be employed in the method ofthe invention include N,N-dimethylcarbamoyl chloride; I N-methyl-N-propylcarbamoyl chloride; N-methyl-N-isopropylcarbamoyl chloride;N-methyl-N-butylcarbamoyl chloride; N,N-dipropylcarbamoyl chloride andthe like. Molar equivalents, or a slight excess of the carbamoylchlorides, and 2-alkylamino-l,3,4 thiadiazole are used in the process.

Metalating agents which may be employed in the invention include sodiummetal, sodium hydride and the like. Molar equivalents of metalatingagent and 2- alkylamino-l,3,4-thiadiazole are used in the process. Themetalating agents employed react with the 2-alkylamino-l,3,4-thiadiazoles wherein the amino hydrogen is replaced bythe metal ion. Solvents suitable for use in the method include inertsolvents used for metalation reactions, for example,N,N-dimethylformamide and tetrahydrofuran.

The reaction generally provides desirable products when conducted in atemperature range of from about -5C w+1 5C and preferably from about Cto about +C.

The method of the invention is particularly suited for preparingl,3,4-thiadiazol-2-ylurea compounds having desirable biologicalactivity, i.e., for us as herbicides, insecticides, fungicides, etc.

The following examples are illustrative of the invention and are notintended to limit the scope thereof.

EXAMPLE 1 Into a three-necked round bottom flask equipped with amagnetic stirrer and through which a slow stream of nitrogen wasintroduced, was added 100 ml of anhydrous N,N-dimethylformamide, 4.6 gmsof N,N-dimethylcarbamoyl chloride and gms of 2-methylamino-S-pentafluoroethyll ,3 ,4-thiadiazole. The reaction mixturewas cooled to 0C and 1.8 gms of a 57 percent suspension in oil of sodiumhydride were added over a period of 2 hours while the reactiontemperature was maintained at 0C to 5C. The mixture was stirred at roomtemperature for about 2 hours, poured into 200 ml of water and the oilwhich separated was extracted with ethyl acetate and the ethyl acetateconcentrated under vacuum to yield an oil product 10 g) which was washedwith petroleum ether. The residue was identified to bel,l,3-trimethyl-3-(5- pentafluoroethyl-l ,3 ,4-thiadiazol-2-yl )urea.

EXAMPLE 2 Into a three-necked round bottom flask, equipped with amagnetic stirrer and through which a slow stream of nitrogen was passed,was added 150 ml of anhydrous N,N-dimethylformamide, g of 5-difluoromethyl-2-methylamino-l ,3,4-thiadiazole and 9.8 g ofN,N-dimcthylcarbamoyl chloride. The reaction mixture was cooled to 0Cand 3.83 g of a 57 percent suspension in oil.of sodium hydride addedover a period of 2 hours while the reaction temperature was kept at 0Cto 5C. The reaction mixture was then stirred at room temperature for 3hours and poured into an icewater mixture. The precipitate which settledwas filtered and taken up in ml of ethyl acetate. The ethylacetate waswashed with water, dried over anhydrous sodium sulfate, and concentratedunder vacuum to give 1 l g of a product identified to bel,l,3-trimethyl-3-(5- difluoromethyl-l ,3,4-thiadiazol-2-yl)urea.

EXAMPLE 3 To a mixture containing 21 gms of 2-methylamino-5- tert.butyl-l,3,4-thiadiazole and l3.2 gms of N,N-dimethylcarbamoyl chloridein mls of anhydrous dimethylformamide, which was kept under anatmosphere of nitrogen and cooled to 5C, was added sodium hydride (5.2 gof a 57 percent suspension in oil) portionwise over a period of one hourwhile the reaction temperature was maintained at ca. 5C. The reactionwas stirred at room temperature for 12 hours, poured into water and themixture extracted with ethyl acetate. The ethyl acetate extract wasdried over anhydrous sodium sulfate and then concentrated to yield anoil which was washed with petroleum ether. The product (24 gms) wasidentified to be l,l,3-trimethyl-3-(5- tert. butyl-l ,3,4-thiadiazol-2-yl )urea.

What is claimed is:

l. A method for producing 1,3,4-thiadiazol-2-ylurea compounds having thegeneral structure:

-NCONR R wherein R, is a lower alkyl radical having from 1 to 4 carbonatoms, a fluoroalkyl radical having from l to 4 carbon atoms, and R Rand R are lower alkyl radicals having from 1 to 4 carbon atoms, whichcomprises reacting a 2-alkylamino-l ,3,4-thiadiazole compound with anN,N-dialkylcarbamoyl chloride compound in the presence of a sodiummetalating agent, the reaction being conducted at a temperature in therange of from about -5C to about +15C.

2. The method of claim 1 wherein the N,N-dialkylcarbamoyl chloridecompound is N,N-dimethylcarbamoyl chloride.

3. The method of claim 1 wherein the sodium metalating agent is sodiumhydride.

4. The method of claim 1 wherein R, is pentafluoroethyl, and R R and R,are methyl.

5. The method of claim 1 wherein R, is difluoromethyl and R R and R, aremethyl.

6. The method of claim 1 wherein R, is tertiary-butyl and R R and R, aremethyl.

1. A METHOD FOR PRODUCING 1,3,4-THIADIAZOL-2-YLUREA COMPOUNDS HAVING THEGENERAL STRUCTURE:
 2. The method of claim 1 wherein theN,N-dialkylcarbamoyl chloride compound is N,N-dimethylcarbamoylchloride.
 3. The method of claim 1 wherein the sodium metalating agentis sodium hydride.
 4. The method of claim 1 wherein R1 ispentafluoroethyl, and R2, R3 and R4 are methyl.
 5. The method of claim 1wherein R1 is difluoromethyl and R2, R3 and R4 are methyl.
 6. The methodof claim 1 wherein R1 is tertiary-butyl and R2, R3 and R4 are methyl.